Shinobu Yasuo, Ayaka Iwamoto, Sang Il Lee, Shotaro Ochiai, Rina Hitachi, Satomi Shibata, Nobuo Uotsu, Chie Tarumizu, Sayuri Matsuoka, Mitsuhiro Furuse, Shigekazu Higuchi, L-serine enhances light-induced circadian phase resetting in mice and humans, Journal of Nutrition, https://doi.org/10.3945/jn.117.255380, 147, 12, 2347-2355, 2017.12, Background: The circadian clock is modulated by the timing of ingestion or food composition, but the effects of specific nutrients are poorly understood. Objective: We aimed to identify the amino acids that modulate the circadian clock and reset the light-induced circadian phase in mice and humans. Methods: Male CBA/N mice were orally administered 1 of 20 L-amino acids, and the circadian and light-induced phase shifts of wheel-running activity were analyzed. Antagonists of several neurotransmitter pathways were injected before L-serine administration, and light-induced phase shifts were analyzed. In addition, the effect of L-serine on the light-induced phase advance was investigated in healthy male students (mean ± SD age 22.2 ± 1.8 y) by using dim-light melatonin onset (DLMO) determined by saliva samples as an index of the circadian phase. Results: L-Serine administration enhanced light-induced phase shifts inmice (1.86-fold; P < 0.05). Both L-serine and its metabolite D-serine, a coagonist of N-methyl-D-aspartic acid (NMDA) receptors, exerted this effect, but D-serine concentrations in the hypothalamus did not increase after L-serine administration. The effect of L-serine was blocked by picrotoxin, an antagonist of γ-aminobutyric acid A receptors, but not by MK801, an antagonist of NMDA receptors. L-Serine administration altered the long-term expression patterns of clock genes in the suprachiasmatic nuclei. After advancing the light-dark cycle by 6 h, L-serine administration slightly accelerated re-entrainment to the shifted cycle. In humans, L-serine ingestion before bedtime induced significantly larger phase advances of DLMO after bright-light exposure during the morning (means ± SEMs-L-serine: 25.9 ± 6.6 min; placebo: 12.1 ± 7.0 min; P < 0.05). Conclusion: These results suggest that L-serine enhances light-induced phase resetting in mice and humans, and it may be useful for treating circadian disturbances..

2.

Tokiho Akiyama, Takafumi Katsumura, Shigeki Nakagome, Sang Il Lee, Keiichiro Joh, Hidenobu Soejima, Kazuma Fujimoto, Ryosuke Kimura, Hajime Ishida, Tsunehiko Hanihara, Akira Yasukouchi, Yoko Satta, Shigekazu Higuchi, Hiroki Oota, An ancestral haplotype of the human PERIOD2 gene associates with reduced sensitivity to light-induced melatonin suppression, PLoS One, https://doi.org/10.1371/journal.pone.0178373, 12, 6, 2017.06, Humans show various responses to the environmental stimulus in individual levels as physiological variations. However, it has been unclear if these are caused by genetic variations. In this study, we examined the association between the physiological variation of response to light-stimulus and genetic polymorphisms. We collected physiological data from 43 subjects, including light-induced melatonin suppression, and performed haplotype analyses on the clock genes, PER2 and PER3, exhibiting geographical differentiation of allele frequencies. Among the haplotypes of PER3, no significant difference in light sensitivity was found. However, three common haplotypes of PER2 accounted for more than 96% of the chromosomes in subjects, and 1 of those 3 had a significantly low-sensitive response to light-stimulus (P < 0.05). The homozygote of the low-sensitive PER2 haplotype showed significantly lower percentages of melatonin suppression (P < 0.05), and the heterozygotes of the haplotypes varied their ratios, indicating that the physiological variation for light-sensitivity is evidently related to the PER2 polymorphism. Compared with global haplotype frequencies, the haplotype with a low-sensitive response was more frequent in Africans than in non-Africans, and came to the root in the phylogenetic tree, suggesting that the low light-sensitive haplotype is the ancestral type, whereas the other haplotypes with high sensitivity to light are the derived types. Hence, we speculate that the high light-sensitive haplotypes have spread throughout the world after the Out-of-Africa migration of modern humans..

3.

Kazuo Isoda, Kana Sueyoshi, Yuki Ikeda, Yuki Nishimura, Ichiro Hisanaga, Stéphanie Orlic, Yeon Kyu Kim, Shigekazu Higuchi, Effect of the hand-omitted tool motion on mu rhythm suppression, Frontiers in Human Neuroscience, https://doi.org/10.3389/fnhum.2016.00266, 10, 2016.06, In the present study, we investigated the effect of the image of hands on mu rhythm suppression invoked by the observation of a series of tool-based actions in a goal-directed activity. The participants were 11 university students. As a source of visual stimuli to be used in the test, a video animation of the porcelain making process for museums was used. In order to elucidate the effect of hand imagery, the image of hands was omitted from the original (“hand image included”) version of the animation to prepare another (“hand image omitted”) version. The present study has demonstrated that, an individual watching an instructive animation on the porcelain making process, the image of the porcelain maker’s hands can activate the mirror neuron system (MNS). In observations of “tool included” clips, even the “hand image omitted” clip induced significant mu rhythm suppression in the right central area. These results suggest that the visual observation of a tool-based action may be able to activate the MNS even in the absence of hand imagery..

4.

Shigekazu Higuchi, Sang Il Lee, Tomoaki Kozaki, Tetsuo Harada, Ikuo Tanaka, Late circadian phase in adults and children is correlated with use of high color temperature light at home at night, Chronobiology International, https://doi.org/10.3109/07420528.2016.1152978, 33, 4, 448-452, 2016.04, Light is the strongest synchronizer of human circadian rhythms, and exposure to residential light at night reportedly causes a delay of circadian rhythms. The present study was conducted to investigate the association between color temperature of light at home and circadian phase of salivary melatonin in adults and children. Twenty healthy children (mean age: 9.7 year) and 17 of their parents (mean age: 41.9 years) participated in the experiment. Circadian phase assessments were made with dim light melatonin onset (DLMO). There were large individual variations in DLMO both in adults and children. The average DLMO in adults and in children were 21:50 ± 1:12 and 20:55 ± 0:44, respectively. The average illuminance and color temperature of light at eye level were 139.6 ± 82.7 lx and 3862.0 ± 965.6 K, respectively. There were significant correlations between color temperature of light and DLMO in adults (r = 0.735, p < 0.01) and children (r = 0.479, p < 0.05), although no significant correlations were found between illuminance level and DLMO. The results suggest that high color temperature light at home might be a cause of the delay of circadian phase in adults and children..

5.

Shigekazu Higuchi, Yuki Nagafuchi, Sang Il Lee, Tetsuo Harada, Influence of light at night on melatonin suppression in children, Journal of Clinical Endocrinology and Metabolism, https://doi.org/10.1210/jc.2014-1629, 99, 9, 3298-3303, 2014.09, Context: The sensitivity of melatonin to light suppression is expected to be higher in children because children have large pupilsandpure crystal lenses. However, melatonin suppression by light in children remains unclear. CopyrightObjective: We investigated whether light-induced melatonin suppression in children is larger than that in adults.Methods: Thirty-three healthy primary school children(meanage, 9.2±1.5 y)and29 healthy adults (meanage, 41.6±4.7 y) participated intwoexperiments. In the first experiment, salivary melatonin concentrations in 13 children and 13 adults were measured at night under a dim light (<30 lux) and a moderately bright light (580 lux) in an experimental facility. Pupil diameters were also measured under dim light and bright light. In the second experiment, melatonin concentrations in 20 children and 16 adults were measured under dim light in the experimental facility and under room light at home (illuminance, 140.0 ± 82.7 lux).Results: In experiment 1, the melatonin concentration was significantly decreased by exposure to moderately bright light in both adults and children. Melatonin suppression was significantly larger in children (88.2%; n = 5) than in adults (46.3%; n = 6; P < .01), although the data for some participants were excluded because melatonin concentrations had not yet risen. In experiment 2, melatonin secretion was significantly suppressed by room light at home in children (n = 15; P < .05) but not in adults (n = 11).Conclusion: We found that the percentage of melatonin suppression by light in children was almost twice that in adults, suggesting that melatonin is more sensitive to light in children than in adults at night..

6.

Shigekazu Higuchi, Akiko Hida, Sei Ichi Tsujimura, Kazuo Mishima, Akira Yasukouchi, Sang Il Lee, Youhei Kinjyo, Manabu Miyahira, Melanopsin Gene Polymorphism I394T Is Associated with Pupillary Light Responses in a Dose-Dependent Manner, PLoS One, https://doi.org/10.1371/journal.pone.0060310, 8, 3, 2013.03, Background: Melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) play an important role in non-image forming responses to light, such as circadian photoentrainment, light-induced melatonin suppression, and pupillary light response. Although it is known that there are some single nucleotide polymorphisms (SNPs) in the melanopsin (OPN4) gene in humans, the associations of the SNPs with non-image forming responses to light remains unclear. In the present study, we examined the associations of melanopsin gene polymorphisms with pupillary light response. Methods: Japanese university students (mean age: 21.0±1.7 years) with the genotypes of TT (n = 38), TC (n = 28) and CC (n = 7) at rs1079610 (I394T) located in the coding region participated in the present study. They were matched by age and sex ratio. Dark-adapted pupil size (<1 lx) was first measured. Then steady-state pupil size was measured during exposure to five lighting conditions (10 lx, 100 lx, 1000 lx, 3000 lx, 6000 lx in the vertical direction at eye level). Results: Significant interaction between the genotype of I394T (TT versus TC+CC) and luminance levels was found in pupil size. Under high illuminance levels (1000 lx, 3000 lx and 6000 lx), pupil sizes in subjects with the C allele were significantly smaller than those in subjects with the TT genotype. On the other hand, pupil size in subjects with the C allele under low illuminance (<1 lx) was significantly larger than that in subjects with the TT genotype. Percentages of pupil constriction under high illuminance levels were significantly greater in subjects with the C allele than in subjects with the TT genotype. Conclusions: Human melanopsin gene polymorphism I394T interacted with irradiance in association with pupil size. This is the first evidence suggesting a functional connection between melanopsin gene polymorphism and pupillary light response as an index of non-image forming response to light..

Shigekazu Higuchi, Yutaka Motohashi, Keita Ishibashi, Takafumi Maeda, Influence of eye colors of Caucasians and Asians on suppression of melatonin secretion by light, American Journal of Physiology - Heart and Circulatory Physiology, https://doi.org/10.1152/ajpregu.00355.2006, 292, 6, 2007.06, This experiment tested effects of human eye pigmentation depending on the ethnicity on suppression of nocturnal melatonin secretion by light. Ten healthy Caucasian males with blue, green, or light brown irises (light-eyed Caucasians) and 11 Asian males with dark brown irises (dark-eyed Asians) volunteered to participate in the study. The mean ages of the light-eyed Caucasians and dark-eyed Asians were 26.4 ± 3.2 and 25.3 ± 5.7 years, respectively. The subjects were exposed to light (1,000 lux) for 2 h at night. The starting time of exposure was set to 2 h before the time of peak salivary melatonin concentration of each subject, which was determined in a preliminary experiment. Salivary melatonin concentration and pupil size were measured before exposure to light and during exposure to light. The percentage of suppression of melatonin secretion by light was calculated. The percentage of suppression of melatonin secretion 2 h after the start of light exposure was significantly larger in light-eyed Caucasians (88.9 ± 4.2%) than in dark-eyed Asians (73.4 ± 20.0%) (P < 0.01). No significant difference was found between pupil sizes in light-eyed Caucasians and dark-eyed Asians. These results suggest that sensitivity of melatonin to light suppression is influenced by eye pigmentation and/or ethnicity..

9.

Shigekazu Higuchi, Yutaka Motohashi, Yang Liu, Akira Maeda, Effects of playing a computer game using a bright display on presleep physiological variables, sleep latency, slow wave sleep and REM sleep, Journal of Sleep Research, https://doi.org/10.1111/j.1365-2869.2005.00463.x, 14, 3, 267-273, 2005.09, Epidemiological studies have shown that playing a computer game at night delays bedtime and shortens sleeping hours, but the effects on sleep architecture and quality have remained unclear. In the present study, the effects of playing a computer game and using a bright display on nocturnal sleep were examined in a laboratory. Seven male adults (24.7 ± 5.6 years old) played exciting computer games with a bright display (game-BD) and a dark display (game-DD) and performed simple tasks with low mental load as a control condition in front of a BD (control-BD) and DD (control-DD) between 23:00 and 1:45 hours in randomized order and then went to bed at 2:00 hours and slept until 8:00 hours. Rectal temperature, electroencephalogram (EEG), heart rate and subjective sleepiness were recorded before sleep and a polysomnogram was recorded during sleep. Heart rate was significantly higher after playing games than after the control conditions, and it was also significantly higher after using the BD than after using the DD. Subjective sleepiness and relative theta power of EEG were significantly lower after playing games than after the control conditions. Sleep latency was significantly longer after playing games than after the control conditions. REM sleep was significantly shorter after the playing games than after the control conditions. No significant effects of either computer games or BD were found on slow-wave sleep. These results suggest that playing an exciting computer game affects sleep latency and REM sleep but that a bright display does not affect sleep variables..

Higuchi S, Effects of light before bed time on melatonin suppression and circadian phase in children , 光生物・光化学応用研究フォーラム, 2014.10.

6.

Higuchi S, Lee Si, Nagafuchi Y, Harada K, ASSOCIATION BETWEEN CIRCADIAN PHASE AND LIGHT BEFORE BEDTIME IN JAPANESE CHILDREN AND THEIR PARENTS, 19th CONGRESS of the EUROPEAN ANTHROPOLOGICAL ASSOCIATION （ヨーロッパ人類学会）, 2014.08.

Lee Si, Higuchi S, Association between genetic polymorphism of melanopsin photoreceptor and sleep/wake timing, 国際人類学民族科学連合(IUAES), 2014.05, The human sleep/wake cycle is adjusted by circadian rhythms that adapt to a 24-hour light/dark cycle. The melanopsin photoreceptor in the retina plays an important role in circadian photoentrainment in the natural environment. However, artificial light at night has adverse effects on human sleep and circadian rhythm in modern society. We have already found that melanopsin gene polymorphism is associated with pupillary light response, but the association with sleep/wake timing has remained unclear. A total of 348 healthy Japanese university students participated in this study. The genotypes of rs1079610 (I394T) located in the coding region were analyzed. Bedtime, wake time and midpoint of sleep on weekdays of CC subjects were significantly later than those of TT and TC subjects. We have already found that pupilloconstriction in subjects with the C allele is highly responsive to light. The delayed sleep/wake timing of CC subjects might be a consequence of the high responsiveness to light at night since exposure to light at night induces phase delay. C allele frequency of I394T in the European population is larger than that in the Asian-Japanese and Sub-saharan African populations. High responsiveness to light may be an adaptive trait for a short photoperiod in European people living in high latitude areas. However, our results suggest that high responsiveness to light is a cause of delayed sleep timing in adolescents living under artificial light at night in modern society..